Synthesis and Biological Activity of 2,22-Dimethylene Analogues of 19-Norcalcitriol and Related Compounds.
J Med Chem
; 63(13): 7355-7368, 2020 07 09.
Article
em En
| MEDLINE
| ID: mdl-32510210
ABSTRACT
Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group attached to C-22 restricts the conformational flexibility of the side chain, which can result in changes in biological characteristics of a molecule. All synthesized 1α,25-dihydroxy-2,22-dimethylene-19-norvitamin D3 analogues proved equal to calcitriol in their ability to bind to the vitamin D receptor, and most of them exert significantly higher differentiation and transcriptional activity than calcitriol. The most active compounds were characterized by the presence of an elongated side chain or 26,27-dimethylene bridge. The synthetic strategy was based on the Wittig-Horner coupling of the known A-ring phosphine oxide with the corresponding Grundmann ketones prepared from a 20-epi-Inhoffen-Lythgoe diol derived from vitamin D2.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Calcitriol
/
Cálcio
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article